Project Summary Rodent-borne viral outbreaks are increasing in both frequency and impact. Hantaviruses are transmitted through the excreta of infected rodents and, when aerosolized, infect humans. In the Americas, hantavirus infection leads to hantavirus cardiopulmonary syndrome (HCPS), a devastating condition that features rapid onset of pulmonary edema, respiratory failure and cardiogenic shock. Treatment is supportive, not pathogen-targeted, and accordingly, approximately 40% of patients do not survive. Because hantaviruses establish lifelong, asymptomatic infections in their rodent reservoirs, they are highly prevalent in nature and represent a constant threat to humans. For example, Sin Nombre virus (SNV), which causes greater than 95% of HCPS cases in North America, is carried by the most abundant mammal on the continent, the deer mouse, which has a near ubiquitous distribution throughout the US and Canada. Despite this large potential for infection and the high case fatality rate, there are no FDA-approved treatment options or vaccines available. Hantaviruses are thus classified as NIAID Priority Pathogens and considered potential bioterrorism threats. Our long term goal is to develop an effective therapeutic against SNV that can be used in the setting of natural exposure to infected rodents or during a bioterrorism attack. The only known correlate of protection against severe HCPS is the development of high titer, virus-specific neutralizing antibodies. Further, immune serum is protective against HCPS disease both animal models and humans. This proposal seeks to capitalize on this knowledge by developing human neutralizing antibodies for therapeutic and/or prophylactic treatment of HCPS caused by SNV. We have assembled a multidisciplinary team of molecular virologists, clinicians, B cell immunologists, and industry partners with experience developing antibody-based therapeutics. In this Phase I application, we will leverage our unique access to SNV patients to i) comprehensively map the antibody repertoire generated during acute SNV infection and ii) identify antibodies that potently neutralize SNV. The successful development of a potent neutralizing antibody against SNV has the potential to be a first-line antiviral for the treatment or prevention of HCPS.